Post-acquisition CO2 Inhalation Enhances Fear Memory and Depends on ASIC1A

Abstract

A growing body of evidence suggests that memories of fearful events may be altered after initial acquisition or learning. Although much of this work has been done in rodents using Pavlovian fear conditioning, it may have important implications for fear memories in humans such as in post-traumatic stress disorder (PTSD). A recent study suggested that cued fear memories, made labile by memory retrieval, were made additionally labile and thus more vulnerable to subsequent modification when mice inhaled 10% carbon dioxide (CO2) during retrieval. In light of this finding, we hypothesized that 10% CO2 inhalation soon after fear acquisition might affect memory recall 24 h later. We found that both cue and context fear memory were increased by CO2 exposure after fear acquisition. The effect of CO2 was time-dependent, as CO2 inhalation administered 1 or 4 h after cued fear acquisition increased fear memory, whereas CO2 inhalation 4 h before or 24 h after cued fear acquisition did not increase fear memory. The ability of CO2 exposure following acquisition to enhance fear memory was not a general consequence of stress, as restraining mice after acquisition did not alter cued fear memory. The memory-enhancing action of CO2 may be relatively specific to fear conditioning as novel object recognition was impaired by post-training CO2 inhalation. To explore the molecular underpinnings of these effects, we tested if they depended on the acid-sensing ion channel-1a (ASIC1A), a proton-gated cation channel that mediates other effects of CO2, likely via its ability to sense acidosis induced during CO2 inhalation. We found that CO2 inhalation did not alter cued or context fear memory in Asic1a–/– mice, suggesting that this phenomenon critically depends on ASIC1A. These results suggest that brain acidosis around the time of a traumatic event may enhance memory of the trauma, and may thus constitute an important risk factor for developing PTSD. Moreover, preventing peritraumatic acidosis might reduce risk of PTSD.

Pharmacokinetics of intranasal amiloride in healthy volunteers

“…Furthermore, the PK profile at higher doses (0.4 and 0.6 mg) shows that amiloride concentrations peak rapidly (within 10 min) after intranasal administration followed by a quick decrease and then the concentrations slowly increase to the initial C max at 24 h. Therefore, with a single intranasal dose we can rapidly achieve concentrations to reduce the panic symptoms and then maintain the anti‐anxiety effect for up to 24 h. This supports the strategy of using intranasal administration as a ready‐to‐use therapeutic to “nip in the bud” an impending panic attack in the real‐world context. Interestingly, CO 2 hypersensitivity is common to panic disorder and post‐traumatic stress disorder, 30 and provided ASICs mediate acute anxiety responses to CO 2 , 10 the amiloride spray‐mediated ASIC inhibition may prove effective for immediate relief both from panic attacks and post‐traumatic stress disorder symptoms.…”

“…Acid‐sensing ion channels (ASICs) are proton‐activated Na + ‐permeable channels that belong to the degenerin/epithelial Na + channel superfamily. 10 ASICs are widely expressed in the brain, including the amygdala, brainstem, and periaqueductal gray. ASICs play a critical role in fear learning and emotional processing.…”